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RAGE deficiency ameliorates autoimmune hepatitis involving inhibition of IL-6 production via suppressing protein Arid5a in mice

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Abstract

Activation of T cells and pro-inflammatory cytokines are essential for human autoimmune hepatitis. RAGE is one of the receptors for the inflammatory alarm molecule high mobility group box 1 (HMGB1), and it is involved in autoimmune hepatitis. However, the molecular mechanism of RAGE in the context of autoimmune hepatitis remains elusive. This study aimed to identify the function and mechanism of RAGE in autoimmune hepatitis. The role and underlying mechanisms of RAGE signaling-driven immune inflammatory response in ConA-induced experimental hepatitis were examined using the RAGE-deficient mice. We found that the RAGE deficiency protected the mouse from liver inflammatory injury caused by the ConA challenge. mRNA expression of VCAM-1, IL-6, and TNF-α within the livers is markedly decreased in RAGE-deficient mice compared to wild-type mice. In parallel, RAGE deficiency leads to reduced levels of the serum pro-inflammatory cytokines IL-6 and TNF-α as compared with wild-type control mice. RAGE-deficient mice exhibit increased hepatic NK cells and decreased CD4+ T cells compared with wild-type control mice. Notably, in vivo blockade of IL-6 in wild-type mice significantly protected mice from ConA-induced hepatic injury. Furthermore, RAGE deficiency impaired IL-6 production and was associated with decreased expression of Arid5a in liver tissues, a half-life IL-6 mRNA regulator. RAGE signaling is important in regulating the development of autoimmune hepatitis. Immune regulation of RAGE may represent a novel therapeutic strategy to prevent immune-mediated liver injury.

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Availability of data and materials

All data used during the current study available from the corresponding author on reasonable request.

Abbreviations

RAGE:

The receptor for advanced glycation end-product

AGEs:

Advanced glycation end products

HMGB1:

High mobility group box 1

AIH:

Autoimmune hepatitis patients

EN-RAGE:

Extracellular newly identified receptor for advanced glycation end products binding protein

sRAGE:

Soluble RAGE

ConA:

Concanavalin A

I/R:

Hepatic ischemia/reperfusion

ALT:

Alanine aminotransferase

AST:

Aspartate aminotransferase

MPO:

Myeloperoxidase

ICAM-1:

Intercellular adhesion molecule-1

VCAM-1:

Vascular cell adhesion molecule-1

WT:

Wild-type mice

Arid5a:

AT-rich interactive domain-containing protein 5a

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Acknowledgements

We thank Mr. Yong Xu and Zhihui Liang for technical assistance with flow cytometry.

Funding

This work was supported by grants from the National Natural Science Foundation of China (91542110, 81373167 to M. Fang).

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Authors and Affiliations

  1. Department of Immunology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, 13# Hangkong Road, Wuhan, 430030, China

    Xiaoxiao Li, Shuyao Hua, Xiaoyuan Fei, Zheng Tan, Fang Zheng, Weimin Wang & Min Fang

  2. Department of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia, SC, USA

    Dai Fang

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  1. Xiaoxiao Li
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  2. Shuyao Hua
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  3. Dai Fang
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  6. Fang Zheng
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  7. Weimin Wang
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  8. Min Fang
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Contributions

XL, DF and MF wrote the main manuscript text. XL, SH, DF, XF, ZT, FZ, WW, MF prepared Figs. 1, 2, 3, 4, 5, 6, 7, 8. All authors reviewed the manuscript.

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Correspondence to Min Fang.

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All animal protocols were approved by the Animal Research Committee at Tongji Medical College Animal Care and Use Committee (Animal permit number S2146).

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Li, X., Hua, S., Fang, D. et al. RAGE deficiency ameliorates autoimmune hepatitis involving inhibition of IL-6 production via suppressing protein Arid5a in mice. Clin Exp Med 23, 2167–2179 (2023). https://doi.org/10.1007/s10238-022-00960-8

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